The prodrug approach to modifying pharmaceuticals in order to overcome one or more undesirable properties of the parent drug has been studied and applied to many compounds in clinical use today. The prodrugs formed are often intended to modify the absorption, metabolism, excretion, toxicity or activity of the parent compound in a desirable way. Additionally, prodrug modifications have been made to some compounds with the goal of creating a drug that is selectively activated or deactivated in a target tissue to increase the specificity of the intended drug effects while decreasing the unintended side effects associated with the parent compound. The prodrug approach has been applied to some of the most successful antibiotics and chemotherapeutic compounds that are designed to be toxic to some living cells and simultaneously non-toxic or much less toxic to other populations of living cells. For example, Doxorubicin (DOX) (CAS No. 25316-40-9) is known as an effective and the most widely used chemotherapeutic agent that has multi-modal cytotoxicity (1-2). Several DOX derivatives have been constructed to date in which those derivatives have demonstrated additional different properties when compared to DOX. Although several derivatives have been found to exhibit greater cytotoxicity than the clinically used anthracyclines, a concomitant increase in systemic toxicity is also commonly observed.
It has been known that Doxorubicin accumulates in cell nuclei. The main cytotoxic actions of doxorubicin occur in the nucleus. After administration, doxorubicin diffuses into cell cytoplasm and enters the nucleus where it binds to topoisomerase and intercalates to the DNA strand. Both nucleolar actions are regarded as the major cytotoxic actions of doxorubicin as well as other anthracycline derivatives (3-5). In addition to nucleolar-specific action, doxorubicin also has multiple cytotoxic actions, especially oxidative stress generation (6-9). However, considering the effects of subcellular distribution of DOX derivatives, it is desirable to have a new derivative having considerable cytotoxicity that can be prevented from entering into the cell nucleus.
It has also been known that bio-conjugation is a process used to attach a bioactive molecule to another molecule via a covalent bond which leads to the formation of a novel chemical structure which may have enhanced properties compared to those of the original molecule. While this process or method has been known, there has not been an attempt in synthesizing a derivative that is capable of functioning as per the need as above mentioned.